Inbred Strains
of Mice: MRL
Inbr (J) 65. Albino:
a,c. Origin: Murphy from crosses started
in about 1960 involving a number of standard inbred strains. Now estimated
to have a composite genome of LG (75%), AKR/J (12.6%), C3H (12.1%) and
C57BL/6 (0.3%). A mutation
lpr (lymphoproliferation) was found
in the 12th. generation of b x s. Homozygotes develop massive generalised
enlargement of the lymph nodes and autoimmunity, and usually die at 14-16
weeks of age.
Characteristics
Origin and characteristics reviewed by Murphy (
1981).
Theofilopoulos et al (
1980) have
compared immune function in this and other autoimmune strains. Behavioural
differences between MRL and MRL-
lpr mice can be detected before
the onset of immunological symptoms in the latter congenic strain (
Sakic et al 1992). The
lpr mutation
is caused by the insertion of of the early transposable element ETn in
the
Fas gene. This causes a striking reduction in
Fas
mRNA expression and is associated clinically with marked acceleration
of the lupus-like disease (
Drappa et al, 1993).
Diethyldithiocarbamate (DTC), an immunomodulative agent which may enhance
T cells, prolongs life in autoimmune MRL-
lpr/lpr mice, but not
in autoimmune NZBxNZWF1 hybrids (
Halpern
and Yocum 1991). Mice with systemic lupus erythematosus (SLE) have
unusual patterns of lymphocyte traffic characterised by diminished uptake
of intravenously injected autoimmune cells into lymph nodes. This appears
to result from defects intrinsic to the lymphocyte population and not
the micro-environment. (
Manolios et al 1990).
Levels of circulating immune complexes rise enormously from about three
months of age in MRL
-lpr/lpr but not in MRL mice. These results
corresponded to histopathological glomerular findings. (
Hewicker et al 1990). Ultrastructural pathology of the
thymic reticulum revealed several features in common with NZB and
BXSB
in varying degrees according to sex and age of the mice. Main anomalies
included vacuolized aspect of the thymic epithelium, an increased number
of macrophages, interdigitating cells and cystic cavities, the presence
of a great number of plasmocytes and mastocytes and extensive interstitial
fibrosis and arteriosclerosis. The most intriguing finding was the presence
of crystal-like inclusions in epithelial cells (
Nabarra
et al 1990). Renal thrombrexane is increased in
lpr/lpr mice,
and this is temporally associated with a decrease in glomerular thrombexane
binding sites without a change in receptor affinity (
Spurney et al, 1993). Homozygous
lpr mice spontaneously
develop lacrimal gland inflamatory lesions and are a model of human Sjogren's
syndrome. These lesions were not decreased by monoclonal anti-CD4 antibodies,
though the morphology was different (
Jabs et
al, 1996). Serum has high concentrations of nitrite/nitrate and peritoneal
cells produce markedly higher levels of interleukin 12 (IL-12) than in
MRL-+/+ controls. The high capacity to produce an enhanced responsiveness
to IL-12 leads to the production of high levels of NO. These are important
contributory factors in the development of autoimmunity (
Huang et al, 1996).
High susceptibility of MRL-lpr to Mycobacterium leprae
(contrast NOD) (Yogi et al 1989). Molecular
heterogeneity of auto-anti-idiotypic antibodies has been studied by Koisumi
et al (1991).
Develop a mild spontaneous arthritis which can be enhanced by intradermal
injection of complete Freund's adjuvant. This appears to be due largely
to background genes rather than lpr (Ratkay
et al, 1994).
Embryonic stem cell lines have been established (Kawase
et al, 1994).
MRL/Mp-+/+ mice develop pancreatitis and sialoadenitis from seven months
of age and also drastic thymic involution. Transplantation of allogeneic
foetal thymus (from C57BL/6 mice) plus either foetal bone marrow or hematopoetic
cells resulted in normal T and B cell function, and the pancreatitis and
sialoadenitis was also fully corrected (Hosaka
et al, 1996).
Maint. by J, Ola.
Drappa
J., Brot N., and Elkon K. B. (1993) The Fas protein is expressed at high
levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal
mice but not in the lupus-prone strain, MRL lpr/lpr. Proceedings of
the National Academy of Sciences of the United States of America
90, 10340-10344.
Halpern
M. D. and Yocum D. E. (1991) The paradoxical effects of diethyldithiocarbamate:
comparisons between New Zealand black/white F1 hybrid and Balb/c mice.
Clin. Immunol. Immunopathol. 58, 69-79.
Hewicker
M., Kromschroder E., and Trautwein G. (1990) Detection of circulating
immune complexes in MRL mice with different forms of glomerulonephritis.
Z. Versuchstierk. 33, 149-156.
Hosaka
N., Nose M., Kyogoku M., Nagata N., Miyashima S., Good R. A., and Ikehara
S. (1996) Thymus transplantation, a critical factor for correction of
autoimmune disease in aging MRL/+ mice. Proceedings of the National
Academy of Sciences of the United States of America 93, 8558-8562.
Huang F.
P., Feng G. J., Lindop G., Stott D. I., and Liew F. Y. (1996) The role
of interleukin 12 and nitric oxide in the development of spontaneous autoimmune
disease in MRL/MP-lpr/lpr mice. Journal Of Experimental Medicine
183, 1447-1459.
Jabs D. A.,
Burns W. H., and Prendergast R. A. (1996) Paradoxic effect of anti-CD4
therapy on lacrimal gland disease in MRL/Mp-lpr/lpr mice. Investigative
Ophthalmology & Visual Science 37, 246-250.
Kawase
E., Suemori H., Takahashi N., Okazaki K., Hashimoto K., and Nakatsuji
N. (1994) Strain difference in establishment of mouse embryonic stem (ES)
cell lines. International Journal of Developmental Biology 38,
385-390.
Manolios
N., Geczy C. L., and Schrieber L. (1990) Aberrant lymphocyte migration
patterns in systemic lupus erythematosus (MRL/l, MRL/n) mice are independent
of the micro-environment. Autoimmunity 7, 139-148.
Murphy E. D. (1981)
Lymphoproliferation (lpr) and other sinbgle-locus models for murine lupus,
in Immunologic defects in laboratory animals Vol. I (Gershwin
M. E. and Merchant B., eds), pp. 143-173. Plenum Press, New York,London.
Nabarra
B., Dardenne M., and Bach J. F. (1990) Thymic reticulum of autoimmune
mice. II: Ultrastructural studies of mice with lupus-like syndrome (NZB,
BXSB, MRL/l). Journal of Autoimmunity 3, 25-36.
Ratkay
L. G., Tait B., Tonzetich J., and Waterfield J. D. (1994) Lpr and MRL
background gene involvement in the control of adjuvant enhanced arthritis
in MRL-lpr mice. Journal of Autoimmunity 7, 561-573.
Sakic B.,
Szechtman H., Keffer M., Talangbayan H., Stead R., and Denburg J. A. (1992)
A behavioral profile of autoimmune lupus-prone MRL mice. Brain Behav.
& Immunity 6, 265-285.
Spurney
R. F., Onorato J. J., Ruiz P., Pisetsky D. S., and Coffman T. M. (1993)
Characterization of glomerular thromboxane receptors in murine lupus nephritis.
J. Pharmacol. Exp. Therapeut. 264, 584-590.
Theofilopoulos A. N., McConahey P. J., Izui S., Eisenberg R. A.,
Pereira A. B., and Creighton W. D. (1980) A comparitive immunologic analysis
of several murine stains with autoimmune manifestations. Clin. Immunol.
Immunopathol. 15, 258-278.
Yogi Y., Nakamura
K., and Suzuki A. (1989) The experimental inoculation with Mycobacterium
leprae in autoimmune mice: results of MRL/lpr mice inoculated into the
right hind foot. Japanese Journal of Leprosy 58, 235-240.
INBRED STRAINS OF MICE
Updated 9 Apr. 1998
Michael FW
Festing
MRC Toxicology Unit, Hodgkin Building,
University of Leicester,
UK
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